Is CDH1 p.Pro488Ala (c.1462C>G) pathogenic?

CDH1 p.Pro488Ala (c.1462C>G) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-18). AlphaMissense: likely benign (0.2368); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Pro488Ala (c.1462C>G)?

CDH1 p.Pro488Ala (c.1462C>G) is associated with hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Pro488Ala (c.1462C>G) in the general population?

CDH1 p.Pro488Ala (c.1462C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH1 p.Pro488Ala (c.1462C>G)?

AlphaMissense predicts likely benign (score 0.2368) — an in-silico prediction, not a clinical call.

CDH1 p.Pro488Ala

c.1462C>G · rs1555516144 · VCV581384

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.2368	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -15.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	8.47e-05%	1,180,044

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDH1
Protein: p.Pro488Ala
Coding: c.1462C>G
MANE Select: NM_004360
dbSNP: rs1555516144
Type: single nucleotide variant
Location: chr16:68815656 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 488: the cadherin 4 domain; a β-strand

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDH1 p.Pro488Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro488= Benign/Likely benign ★★ same residue
CDH1 p.Pro488Arg Uncertain significance ★ same residue
CDH1 p.Pro488Thr Uncertain significance ★ ⚠ same residue
CDH1 c.1008+2T>C Likely pathogenic ★★★ same condition
CDH1 c.1137+1G>A Pathogenic ★★★ same condition
CDH1 c.1137+2T>C Likely pathogenic ★★★ same condition
CDH1 c.1320+1G>C Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdh1-p-pro488ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown